Epidemiology and outcomes Sci Med: first published as 10.1136/lupus-2020-000411 on 22 September 2020. Downloaded from Cutaneous in SLE

Romy Kallas ‍ ,1 Daniel Goldman,2 Michelle A Petri ‍ 1

To cite: Kallas R, Goldman D, ABSTRACT .1–3 Among juvenile patients with Petri MA. Cutaneous vasculitis in Objectives We determined the temporal association SLE, those with acute cutaneous lupus erythe- SLE. Lupus Science & Medicine between clinical and serological manifestations matosus or non-scarring­ alopecia were more 2020;7:e000411. doi:10.1136/ and development of cutaneous small vessel vasculitis in a lupus-2020-000411 likely to develop , while mucosal large prospective multiethnic cohort. ulcers were associated with a higher of Methods Patients with SLE diagnosed according to the leucopenia.1 In adult patients with SLE, the Systemic Lupus International Collaborating Clinics (SLICC) Received 24 April 2020 presence of malar was indicative of more Revised 17 August 2020 classification criteria or the revised classification criteria Accepted 24 August 2020 as defined by the American College of (ACR) severe , while discoid lupus were enrolled in the Hopkins Lupus Cohort. Cutaneous appeared to be associated with a decreased 2 3 small vessel vasculitis was determined as a component of incidence of renal disease but an increased the Systemic Disease Activity Index. Systemic Lupus International Collaborating SLE-­associated cutaneous small vessel vasculitis lesions Clinics/American College of Rheumatology were reported clinically. They presented as punctate Damage Index (SLICC/ACR DI).3 lesions, palpable , tender erythematous plaques Cutaneous small vessel vasculitis is a non-­ or macules with or without . No histopathological specific cutaneous manifestation and is diagnosis was pursued to confirm the diagnosis of the most frequent type of vasculitis among vasculitis or to differentiate it from other causes of digital 4 5 lesions in patients with SLE. Disease manifestations patients with SLE. It is mostly limited that preceded the first occurrence of cutaneous small and is infrequently associated with systemic 5 6 4 5 7 vessel vasculitis lesions were analysed using Kaplan-­ vasculitis. It is seen in up to 20%. Cuta- Meier. Cox regression analysis was used to assess the neous small vessel vasculitis mostly pres- relationship between baseline clinical and immunological ents as punctate lesions, , manifestations and the development of cutaneous small ulcers, erythematous plaques or macules and vessel vasculitis. We adjusted for gender, race and age at with necrosis that may occur once SLE diagnosis. or may be relapsing.5 Results A total of 2580 patients were studied: 52.4% were Caucasian and 39.4% were African-­American. In the setting of Sjögren’s syndrome, devel- The mean age of the cohort was 45.5±14.5 years. The opment of cutaneous vasculitis signified more http://lupus.bmj.com/ mean years of cohort follow-­up was 7.9±7.6. Cutaneous severe disease, including higher rates of joint small vessel vasculitis was observed in 449 (17.3%). The disease, , renal involve- mean time to cutaneous vasculitis after SLE diagnosis ment, , hospitalisation and even was 4.78 years (95% CI 3.96 to 5.60). At least 159 (35%) death.8 In the setting of rheumatoid , patients had recurrences of cutaneous vasculitis lesions. leucocytoclastic vasculitis had an unfavourable Discoid rash, Raynaud’s phenomenon, , anaemia, prognosis with associations with mononeuritis Coombs’ positivity, leucopenia, anti-­Smith and anti-RNP­ 9 multiplex and bowel involvement. on September 27, 2021 by guest. Protected copyright. (Ribonucleoprotein) were significantly associated with the development of cutaneous vasculitis. The SLICC/ACR In SLE, past studies evaluated the clinical Damage Index score was higher in patients with cutaneous and serological characteristics of patients vasculitis compared with those without cutaneous with combined cutaneous and visceral vascu- 4 5 10–12 vasculitis. litis. In these studies, SLE patients with © Author(s) (or their employer(s)) 2020. Re-­use Conclusions Cutaneous vasculitis is frequent (17.3%) vasculitis were found to be mostly men, were 13 permitted under CC BY-­NC. No and often recurrent (35%). African-­Americans are at higher younger at SLE onset, had longer disease commercial re-­use. See rights risk of developing cutaneous small vessel vasculitis than duration, , haematolog- and permissions. Published by Caucasians. Clinical presentations such as myositis and ical parameters ( and high Erythro- BMJ. haematological manifestations are predictors of cutaneous 10 4 1 cyte Sedimentation Rate), anti-­dsDNA, Division of Rheumatology, vasculitis development. The presence of cutaneous 11 5 12 Johns Hopkins Medicine, vasculitis is associated with increased organ damage. anti-SSA, anti-­SSB and anti-­Smith. Baltimore, Maryland, USA However, only 2% of patients with SLE have 2Department of Rheumatology, concomitant visceral and cutaneous vascu- Johns Hopkins University, litis.5 6 Moreover, as detailed in the Derma- Baltimore, Maryland, USA I- INTRODUCTION tologic Addendum to the 2012 Revised Correspondence to Lupus-­specific cutaneous manifestations International Chapel Hill Consensus Confer- Dr Romy Kallas; ​kallasr@mlhs.​ ​ are important in relation to the develop- ence Nomenclature of Vasculitides, the org ment of systemic involvement and ultimate presentation of cutaneous vasculitis occurring

Kallas R, et al. Lupus Science & Medicine 2020;7:e000411. doi:10.1136/lupus-2020-000411 1 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2020-000411 on 22 September 2020. Downloaded from in patients with SLE is heterogeneous but is mostly small livedo and Raynaud’s phenomenon. The musculoskel- vessel vasculitis rather than medium vessel.14 Therefore, etal manifestations included and arthritis. studies of cutaneous small vessel vasculitis are more rele- The renal data included , haematuria, renal vant to clinical practice. insufficiency and renal failure. The neuropsychiatric One study of juvenile SLE patients with cutaneous manifestations included , , , vasculitis alone found that it was associated with more , lupus , , mononeuritis and granular casts.1 In adult patients with SLE, multiplex, cognitive impairment, , cranial having cutaneous vasculitis was associated with Raynaud’s neuropathy, peripheral neuropathy, longitudinal phenomenon,15 mucocutaneous and musculoskeletal or brain CT/MRI abnormalities. The haematological manifestations,7 myositis1 or no major organ involve- data included anaemia defined as haemoglobin less than ment.15 Cutaneous vasculitis was also found to correlate 11.0 g/dL in a woman and less than 12.0 g/dL in men, with disease activity1 5 7 16 and poor prognosis with renal haemolytic anaemia, leucopenia defined as white blood system and (CNS) deterioration.16 cell count (WBC) <4000 documented two or more times Patients with cutaneous vasculitis were more likely to have when the patient was not on drugs known to cause bone antiribosomal P ,15 anti-Ro­ antibody11 and cryo- marrow suppression and thrombocytopaenia defined as globulins.17 One study of patients with SLE reported an platelets <100 000, which was not due to medications. association with hypocomplementaemia and antiphos- Cardiac manifestations included , Libman-­ pholipid syndrome.7 Sacks and cardiac murmur. Pulmonary manifestations The aim of this study was to determine the association included fibrosis and pulmonary . Gastroin- between clinical and serological manifestations of SLE testinal manifestations included hepatomegaly, increased and development of future cutaneous small vessel vascu- , , gastrointestinal lupus litis, as well as the association between the presence of and . Sjögren’s syndrome was diagnosed cutaneous vasculitis and organ damage in a large prospec- in the presence of dry eyes confirmed by an abnormal tive multiethnic cohort. Schirmer test and/or low ocular surface staining not due to or dry eyes and dry mouth in the presence of anti-Ro­ and/or La antibodies. We also included venous PATIENTS AND METHODS and arterial . The Hopkins Lupus Cohort is a longitudinal cohort The immunological data included anti-dsDNA,­ anti-­ of patients diagnosed with SLE at the Hopkins Lupus Smith, anti-­RNP, anti-­SSA, anti-­SSB, Center. All patients gave written informed consent to (by International Society on Thrombosis and Haemo- participate. Patients were followed up by protocol quar- stasis definitions), anticardiolipin IgG and IgM, anti-­ terly or more often as clinically indicated. A total of 2580 beta-2 IgG and IgM, C3 and C4 level and patients with SLE diagnosed according to the SLICC clas- CH50. 18 sification criteria or the revised classification criteria as The SLICC/ACR DI was used to measure damage, http://lupus.bmj.com/ defined by the ACR.19 20 defined as irreversible organ dysfunction, present for 6 months or longer, regardless of aetiology, in all organ Variables systems.21 The SLICC/ACR DI was calculated based on Cutaneous vasculitis was defined clinically by the presence organ damage accumulated since the onset of SLE until of cutaneous small vessel vasculitis lesions documented on the last visit. the Systemic Lupus Erythematosus Disease Activity Index The socioeconomic–demographic factors included

(SLEDAI) score by one rheumatologist (MAP) during gender (female or male), race (Caucasian, African-­ on September 27, 2021 by guest. Protected copyright. physical examination. Cutaneous small vessel vasculitis American, Asian, Hispanic or others), age at last visit as lesions were reported as part of the SLEDAI score in our a continuous variable, education (categorised into less or cohort. They presented as punctate lesions, palpable equal to 12 years and more than 12 years) and annual purpura, tender erythematous plaques or macules with household income as a continuous variable. or without necrosis. In our patients presenting with these lesions, the diagnosis was made clinically, and no histo- Statistical analysis pathological diagnosis was pursued. We used the date SLE manifestations that preceded the first occurrence of of first appearance of the cutaneous vasculitis in our cutaneous vasculitis were analysed using Kaplan-Meier­ . To analysis. We excluded patient who developed cutaneous assess the temporal relationship between clinical/immu- vasculitis before SLE diagnosis as the baseline variables nological manifestations and development of cutaneous were recorded at the time of SLE diagnosis. vasculitis, Cox regression analysis was done and adjusted The clinical data included cutaneous, musculoskel- for gender, race and age at SLE diagnosis. The relation- etal, , renal, neuropsychiatric, haematological, ship between socioeconomic–demographic variables was cardiac, pulmonary and gastrointestinal manifestations examined by Student’s t-test­ or Fisher’s t-tests­ as appro- of SLE. The date of first appearance of each manifesta- priate. A p value of less than 0.05 was used to determine tion was used. The cutaneous manifestations included significance. All analyses were performed using JMP, , discoid lupus, oral ulcers, photosensitivity, V.13.0.

2 Kallas R, et al. Lupus Science & Medicine 2020;7:e000411. doi:10.1136/lupus-2020-000411 Epidemiology and outcomes Lupus Sci Med: first published as 10.1136/lupus-2020-000411 on 22 September 2020. Downloaded from

Table 1 Demographics and socioeconomic status of SLE patients with and without cutaneous vasculitis With cutaneous vasculitis Without cutaneous vasculitis Factor (n=449) (n=2131) OR (95% CI) P value Gender (male) 6.7% 8.1% 0.82 (0.55 to 1.22) 0.3840 Race (African-­American) 46.3% 42.2% 1.18 (0.95 to 1.46) 0.1404 Smoking ever 39.5% 34.7% 1.23 (0.997 to 1.52) 0.0573 Alcohol abuse ever 6.9% 6.6% 1.05 (0.71 to 1.58) 0.8346 Drug abuse ever 7.1% 5.8% 1.24 (0.83 to 1.86) 0.3264 Age at cohort entry 41.6±13.0 41.2+12.4 0.6974 Age at SLE diagnosis 30.4±12.8 32.6+13.0 0.0020

Values are expressed as mean±SD or percentage.

III- RESULTS cutaneous small vessel vasculitis. Only 13% (253/1991) From 1987 to 2019, there were 2580 patients with SLE. and 5% (111/2256) of patients with anti-­Ro and anti-­La, The cumulative classification criteria were 48.2% malar respectively, developed vasculitic lesions. Moreover, only rash, 19.1% discoid rash, 51.5% photosensitivity, 52.5% a minority of patients with low C3 (9%, 245/2746) or low oral , 71.6% arthritis, 42.9% serositis, 45.2% - C4 (18%, 321/1809) developed cutaneous small vessel uria, 47.2% leucopenia, 20.2% and vasculitis. 96.5% ANA positivity based on revised ACR classifica- The SLICC/ACR DI score was higher in patients with tion criteria.22 Additional SLICC classification criteria cutaneous vasculitis compared with those without cuta- included 20.8% direct Coombs’ test, 54.8% low C3, neous vasculitis. Patients with cutaneous vasculitis had 47.6% low C4 and 16.2% low CH50.18 Among the 2580 a SLICC/ACR DI score of 3.53±3.25 compared with patients, there were 92.2% female, 7.8% males, 52.4% 2.19±2.5 in patients without cutaneous vasculitis (p value Caucasian and 39.4% African-American.­ The mean age of <0.0001). the cohort was 45.5±14.5 years. The mean years of cohort follow-­up was 7.9±7.6 (range 0–32.2 years), and the mean years of follow-­up after SLE diagnosis was 13.2±9.7 (range IV- DISCUSSION 0–57 years). We excluded 61 patients in whom cutaneous In this study, we found that presence of cutaneous small vasculitis occurred prior to SLE diagnosis. vessel vasculitis was associated with both mild and severe Cutaneous vasculitis was observed in 17.3% of patients disease manifestations. Mucocutaneous and haematolog- with SLE. The mean time to cutaneous vasculitis after SLE ical manifestations, myositis, Raynaud’s phenomenon, http://lupus.bmj.com/ diagnosis was 4.78 years (95% CI 3.96 to 5.60). Among anti-­Smith and anti-­RNP were predictors of the develop- patients who developed cutaneous vasculitis, 50% had the ment of later cutaneous small vessel vasculitis. In addi- onset by 2 years after their SLE diagnosis and 75% by 10 tion, SLE patients with cutaneous vasculitis were found to years after their diagnosis. At least 159 out of 449 (35%) have an increased risk of organ damage overall. patients had two or more cutaneous vasculitis events. First, the of cutaneous vasculitis in our Table 1 shows the socioeconomic-demographic­ features cohort was around 18%. In a cohort of 667 patients with in patients with SLE included in this analysis. There were SLE of Hispanic decent, the prevalence of cutaneous on September 27, 2021 by guest. Protected copyright. no significant differences observed for gender, race, vasculitis was similar at 23%.4 In a cohort of 670 patients socioeconomic status (defined by income and years of with SLE of European decent, 76 (11%) patients were education), smoking or alcohol abuse. The age at SLE reported to have vasculitis (either visceral or cutaneous).5 diagnosis was younger in those with cutaneous vasculitis The increased risk of cutaneous vasculitis in African-­ compared with those without cutaneous vasculitis (30.4 vs American patients is a novel finding that has not been 32.6 with a p value of 0.002). previously reported. African-American­ patients had a Table 2 outlines the clinical and immunological manifes- 20% higher likelihood of developing cutaneous vasculitis tations as predictors of development of cutaneous vascu- compared with Caucasian patients in our analysis. This litis before and after adjustment for gender, race and age supports the role of race and hence genetic factors in at SLE diagnosis. Discoid rash, Raynaud’s phenomenon, determining disease manifestations in SLE. Few studies myositis, anaemia, Coombs’ positivity, leucopenia, anti-­ have looked at the rate of recurrence of cutaneous vascu- Smith and anti-RNP­ were significantly associated with the litis in patients with SLE. We report that at least 35% of development of cutaneous vasculitis. African-­American patient with cutaneous vasculitis had a recurrent episode patients had a 25% higher likelihood of developing cuta- during their disease course. A study by Drenkard et al4 neous vasculitis compared with Caucasian patients (HR reported that, among 194 patients with either cutaneous 1.26, 95% CI 1.02 to 1.55). There was no association or visceral vasculitis, 75 (38%) had two or more vasculitis with anti-Ro­ or anti-La­ positivity and the development of events.

Kallas R, et al. Lupus Science & Medicine 2020;7:e000411. doi:10.1136/lupus-2020-000411 3 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2020-000411 on 22 September 2020. Downloaded from

Table 2 Clinical and immunological manifestations as predictors of development of cutaneous vasculitis Factor HR (95% CI) P value HR (95% CI) adjusted* P value adjusted* Gender (male) 0.74 (0.47 to 1.10) 0.1452 Race (African-­American) 1.26 (1.02 to 1.55) 0.0315 Age at SLE diagnosis 0.99 (0.98 to 1.00) 0.0996 Post-­high school education 0.76 (0.62 to 0.94) 0.0099 0.76 (0.61 to 0.94) 0.0125 (>12 years) Malar rash 1.04 (0.84 to 1.28) 0.7077 1.03 (0.83 to 1.28) 0.7801 Discoid rash 1.38 (1.04 to 1.81) 0.0274 1.27 (0.94 to 1.70) 0.1202 Photosensitivity 0.90 (0.72 to 1.10) 0.2996 0.90 (0.72 to 1.13) 0.3815 1.22 (0.98 to 1.51) 0.0732 1.22 (0.97 to 1.53) 0.0898 Alopecia 1.18 (0.95 to 1.47) 0.1336 1.09 (0.87 to 1.38) 0.4361 Raynaud’s phenomenon 1.35 (1.10 to 1.67) 0.0049 1.35 (1.09 to 1.68) 0.0075 Arthritis 1.04 (0.85 to 1.27) 0.7361 1.07 (0.87 to 1.32) 0.5206 Myositis 2.18 (1.12 to 3.77) 0.0236 2.13 (1.05 to 2.80) 0.0366 Pleuritis 1.17 (0.91 to 1.49) 0.2219 1.16 (0.90 to 1.50) 0.2487 1.25 (0.89 to 1.72) 0.1880 1.24 (0.87 to 1.71) 0.2321 Proteinuria 1.09 (0.85 to 1.40) 0.4851 1.15 (0.88 to 1.49) 0.3050 Anaemia 1.35 (1.08 to 1.68) 0.0090 1.39 (1.10 to 1.75) 0.0063 Haemolytic anaemia 1.35 (0.80 to 2.13) 0.2478 1.40 (0.82 to 2.20) 0.2022 Coombs ever 1.57 (1.07 to 2.24) 0.0212 1.53 (1.03 to 2.20) 0.0366 Leucopenia 1.38 (1.09 to 1.73) 0.0078 1.39 (1.09 to 1.77) 0.0089 Thrombocytopaenia 0.81 (0.55 to 1,15) 0.2418 0.84 (0.56 to 1.22) 0.3787 Anti-­dsDNA ever 1.19 (0.95 to 1.49) 0.1227 1.23 (0.97 to 1.55) 0.0868 Anti-­Sm ever 1.53 (1.10 to 2.06) 0.0112 1.59 (1.14 to 2.17) 0.0076 Anti-­Ro ever 1.31 (0.93 to 1.79) 0.1223 1.24 (0.85 to 1.74) 0.2485 Anti-­La ever 1.29 (0.79 to 1.99) 0.2947 1.31 (0.77 to 2.07) 0.2964 Anti-­RNP ever 1.65 (1.19 to 2.25) 0.0033 1.56 (1.09 to 2.17) 0.0151 http://lupus.bmj.com/ Low C3 ever 1.19 (0.87 to 1.61) 0.2716 1.26 (0.90 to 1.73) 0.1743 Low C4 ever 1.13 (0.81 to 1.55) 0.4609 1.21 (0.85 to 1.69) 0.2781 Russell Viper Venom Time (RVVT) 0.85 (0.48 to 1.37) 0.5269 0.85 (0.46 to 1.43) 0.5714 ever Anti-­cardiolipin ever 1.09 (0.77 to 1.48) 0.6271 1.18 (0.83 to 1.64) 0.3406 Anti-­beta 2 GPI ever 0.35 (0.06 to 1.11) 0.0797 0.24 (0.01 to 1.06) 0.0630 on September 27, 2021 by guest. Protected copyright. *Adjusted for gender, race and age at SLE diagnosis.

Second, our study showed that the presence of discoid Haematological manifestations such as anaemia, rash predicted an increased risk of development of cuta- direct Coombs’ positivity and leucopenia were found neous vasculitis. The association between discoid rash to be risk factors for developing cutaneous vasculitis and vasculitis has been reported by Santiago-Casas­ et al3 in our study. Gheita et al7 had also reported an asso- in a large multiethnic, multicentre cohort of patients with ciation between anaemia and cutaneous vasculitis. In SLE. A large cross-­sectional study of childhood SLE deter- Ramos-­Casals et al’s5 study, 67% of patients with vascu- mined an association between cutaneous vasculitis and litis (visceral or cutaneous) were reported to be anaemic other mucocutaneous manifestations including discoid compared with 17% of patients with no vasculitis. Looking rash, acute cutaneous rash and photosensitivity.23 In addi- at the SLEDAI parameters, Gomes et al 24 reported an tion, Gomes et al24 reported that acute cutaneous rash, association with leucopenia but not thrombocytopaenia. alopecia and oral ulcers were associated with cutaneous A more serious manifestation, myositis, was shown in vasculitis. A small retrospective study of 50 patients with our study as predicting later cutaneous vasculitis. A retro- SLE in Egypt found an association between combined spective study of 206 adult and 171 juvenile patients with mucocutaneous manifestations and cutaneous vasculitis.7 SLE of Southeast Asian descent, with a mean follow-up­ of 8

4 Kallas R, et al. Lupus Science & Medicine 2020;7:e000411. doi:10.1136/lupus-2020-000411 Epidemiology and outcomes Lupus Sci Med: first published as 10.1136/lupus-2020-000411 on 22 September 2020. Downloaded from years, had reported the association of cutaneous vasculitis antibodies) that result in occlusion of dermal blood and myositis only in adult patients.1 Cutaneous vasculitic vessels with fibrin thrombi.29 features in adult inflammatory without SLE Fourth, in terms of associations, anti-­Smith have been reported. In a retrospective study of 76 patients and anti-RNP­ were found to be significant risk factors for with and followed-up­ over cutaneous vasculitis. Anti-RNP­ is a novel finding that has an 11-year­ period, 9% had cutaneous vasculitis.25 In addi- not been previously reported. Only one small retrospec- tion, two studies found cutaneous vasculitis in patients tive study (evaluating 34 patients), in 1983, found an asso- 12 with myositis to be a predictor of malignancy.25 26 Inter- ciation between anti-­Smith and cutaneous vasculitis. An 15 estingly, one study showed that vasculitic skin lesions were association between anti-P­ antibodies and cutaneous 15 23 associated with muscle vasculitis on muscle .26 vasculitis but not the other has been We did not find an association between other major reported. Although some studies suggested an association organ involvement and cutaneous vasculitis. All clinical between cutaneous vasculitis and Sjögren’s syndrome or 7 8 11 manifestations including renal and CNS involvements anti-­SSA/SSB antibodies, our study did not find an were similar in SLE patients with or without cutaneous association with secondary Sjögren’s syndrome in SLE. vasculitis in two cross-sectional­ studies from Brazil evalu- No patients with primary Sjögren’s syndrome and hyper- ating both adult (comparing 91 patients with cutaneous gammaglobulinaemia were included. vasculitis to 163 patients without cutaneous vasculitis15) Fifth, we did not find an association between hypoco- mplementaemia or anti-dsDNA­ and cutaneous vasculitis. and juvenile patients with SLE (a cohort of 852 patients, 5 of which 25 had cutaneous vasculitis23). A study that Hypocomplementaemia and high disease activity have been reported to be associated with cutaneous vascu- examined the association between digital vasculitis as 4 7 17 defined by the SELENA-SLEDAI­ score and lupus severity litis. A higher mean European Consensus Lupus in 168 patients with SLE determined that digital vascu- Activity Measurement (ECLAM) score was reported in litis was not associated with severe lupus manifestations, patients with vasculitis, 90% of which were cutaneous. particularly renal and CNS.24 However, Callen et al16 had The mean ECLAM score was 5.86 in patients with vascu- litis compared with 3.87 in those without vasculitis.5 This reported in 1983 that cutaneous vasculitis correlated with was not confirmed in a study that looked at childhood active systemic lupus and portended a poor prognosis. SLE patients with digital vasculitis. The SLEDAI median, A patient with several vasculitic changes on the fingers after excluding the vasculitis descriptor, was significantly died of progressive renal and CNS deterioration.16 A lower in patients with digital vasculitis compared with retrospective analysis of 171 juvenile patients with SLE of those without this manifestation (10 vs 14, p=0.004).23 Asian descent found an increased risk of renal and neuro- Moreover, Gomes et al, who specifically looked at SLEDAI psychiatric manifestations in patients who have cutaneous parameters associated with digital vasculitis, did not find vasculitis compared with those who did not.1 Gheita et al7 low complement levels or high anti-dsDNA­ in patients who had reported an association between cutaneous vasculitis 24 presented with digital vasculitis. This study suggested http://lupus.bmj.com/ and lupus in a small retrospective study from that the high weight attributed to cutaneous vasculitis in Egypt evaluating 50 adult patients with SLE. Our study, the SLEDAI score should be reevaluated.24 the largest overall and the only one with long follow-up,­ Sixth, patients with cutaneous vasculitis had higher did not show any association between cutaneous vasculitis SLICC/ACR DI scores compared with those without. In and CNS or renal lupus. fact, in a study of childhood SLE, the presence of cuta- Third, considering the possibility of vasculopathy in neous vasculitis was associated with permanent damage 23 patients with SLE, our study showed that only Raynaud’s in 20% of the patients. In a study looking at both cuta- on September 27, 2021 by guest. Protected copyright. phenomenon predicted the development of cutaneous neous and visceral vasculitis, patients with visceral but not vasculitis. We found no association between cutaneous cutaneous vasculitis had a higher mortality compared vasculitis and antiphospholipid antibodies, livedo reticu- with patients without vasculitis.4 laris, arterial or . This is in accordance We did not subdivide into subtypes such as palpable with a study of 852 patients with childhood SLE in which purpura, ulcers and erythema with or without necrosis. none of the patients with cutaneous vasculitis had anti- are not done as part of routine practice. Patients phospholipid syndrome or thrombotic thrombocyto- were treated at presentation with a clinical diagnosis 23 paenic purpura. Two other studies, though, suggested of small vessel vasculitis. Small vessel vasculitis may be antiphospholipid antibodies and vasculopathy as players overestimated based on clinical presentation alone.30 in the mechanism for cutaneous vasculitis in patients with The of digital cutaneous lesions 4 7 SLE. It is important to note that non-­vasculitic occlusive includes discoid lupus erythematous and non-occlusive­ 27 vasculopathy might mimic vasculitis lesions. Vasculitis is vasculopathy, among others. As we found no association characterised by an inflammatory process involving infil- with antiphospholipid antibodies, it is unlikely that non-­ tration of the vessel walls by leucocytes with subsequent occlusive vasculopathy was a major limitation. Biopsies endothelial damage and .28 Vasculop- can differentiate between the different types of cuta- athy is characterised by non-inflammator­ y lesions due to neous vasculitis that can be seen in patients with SLE.14 (such as the presence of antiphospholipid Despite these limitations, all diagnoses were made by

Kallas R, et al. Lupus Science & Medicine 2020;7:e000411. doi:10.1136/lupus-2020-000411 5 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2020-000411 on 22 September 2020. Downloaded from one rheumatologist with expertise in SLE. Our database 6 Brandt JT, Triplett DA, Alving B, et al. Criteria for the diagnosis of lupus anticoagulants: an update. on behalf of the Subcommittee recorded ‘vasculitis’ as part of the SLEDAI. on lupus Anticoagulant/Antiphospholipid of the scientific and standardisation Committee of the ISTH. Thromb Haemost 1995;74:1185–90. CONCLUSION 7 Gheita TA, Abaza NM, Sayed S, et al. Cutaneous vasculitis in systemic lupus erythematosus patients: potential key players and This is the largest prospective multiethnic study with implications. Lupus 2018;27:738–43. long-­term follow-­up examining the clinical and serolog- 8 Ramos-­Casals M, Anaya J-­M, García-­Carrasco M, et al. Cutaneous ical associations of cutaneous vasculitis in patients with vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients. Medicine 2004;83:96–106. SLE. Our study determined the increased risk of cuta- 9 Chen K-­R, Toyohara A, Suzuki A, et al. Clinical and histopathological neous vasculitis in African-American­ race and the consid- spectrum of cutaneous vasculitis in . Br J erable risk of recurrence of this manifestation. It high- Dermatol 2002;147:905–13. 10 López-­Longo FJ, González Fernández CM, Rodríguez Mahou lights the temporal association between the development M, et al. [Clinical expression of systemic lupus erythematosus of cutaneous vasculitis and clinical manifestations such as with anti-­U1-­RNP and anti-­Sm antibodies]. Rev Clin Esp 1997;197:329–35. discoid rash, Raynaud’s phenomenon, myositis, anaemia, 11 Fukuda MV, Lo SC, de Almeida CS, et al. Anti-­Ro antibody and Coombs’ positivity, leucopenia and immunological mani- cutaneous vasculitis in systemic lupus erythematosus. Clin festations such as anti-­Smith and anti-­RNP positivity. Rheumatol 2009;28:301–4. 12 Beaufils M, Kouki ,F Mignon F, et al. Clinical significance of anti-­ Our study did not find any association between cuta- Sm antibodies in systemic lupus erythematosus. Am J Med neous vasculitis and either antiphospholipid antibodies 1983;74:201–5. 13 Dimant J, Ginzler EM, Schlesinger M, et al. Systemic lupus or Sjögren’s syndrome. Our study stresses on the impor- erythematosus in the older age group: computer analysis. J Am tance of cutaneous vasculitis as a disease manifestation, Geriatr Soc 1979;27:58–61. considering its association with increased organ damage. 14 Sunderkötter CH, Zelger B, Chen K-­R, et al. Nomenclature of cutaneous vasculitis: dermatologic addendum to the 2012 revised international chapel Hill consensus conference Nomenclature of Contributors RK contributed to the conception, design, interpretation of the vasculitides. Arthritis Rheumatol 2018;70:171–84. data and writing of the manuscript. DG contributed to the design, analysis and 15 Shinjo SK, Bonfá E. Cutaneous vasculitis in systemic lupus interpretation of the data. MAP contributed to the collection of cohort data, erythematosus: association with anti-­ribosomal P protein antibody conception, design, interpretation of the data and writing of the manuscript. and Raynaud phenomenon. Clin Rheumatol 2011;30:173–7. 16 Callen JP, Kingman J. Cutaneous vasculitis in systemic lupus Funding The Hopkins Lupus Cohort was funded by NIH Grant R01-­AR069572. erythematosus. A poor prognostic indicator. Cutis 1983;32:433–6. Competing interests None declared. 17 García-­Carrasco M, Ramos-­Casals M, Cervera R, et al. in systemic lupus erythematosus: prevalence and Patient and public involvement Patients and/or the public were not involved in clinical characteristics in a series of 122 patients. Semin Arthritis the design, or conduct, or reporting, or dissemination plans of this research. Rheum 2001;30:366–73. Patient consent for publication Not required. 18 Petri M, Orbai A-­M, Alarcón GS, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria Ethics approval The cohort was established in 1987 and has been approved by for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86. the Johns Hopkins University School of Medicine Institutional Review Board on a 19 Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the yearly basis. classification of systemic lupus erythematosus. Arthritis Rheum Provenance and peer review Not commissioned; externally peer reviewed. 1982;25:1271–7.

20 Hochberg MC. Updating the American College of rheumatology http://lupus.bmj.com/ Data availability statement Data are available on reasonable request. revised criteria for the classification of systemic lupus Open access This is an open access article distributed in accordance with the erythematosus. Arthritis Rheum 1997;40:1725. Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 21 Gladman DD, Urowitz MB. The SLICC/ACR damage index: progress permits others to distribute, remix, adapt, build upon this work non-commercially­ , report and experience in the field. Lupus 1999;8:632–7. and license their derivative works on different terms, provided the original work is 22 Hochberg MC, Chang RW, Dwosh I, et al. The American College of rheumatology 1991 revised criteria for the classification of properly cited, appropriate credit is given, any changes made indicated, and the use global functional status in rheumatoid arthritis. Arthritis Rheum is non-­commercial. See: http://​creativecommons.org/​ ​licenses/by-​ ​nc/4.​ ​0/. 1992;35:498–502. 23 Sakamoto AP, Silva CA, Silva MFCda, et al. Initial digital vasculitis ORCID iDs in a large multicenter cohort of childhood-­onset systemic lupus on September 27, 2021 by guest. Protected copyright. Romy Kallas http://orcid.​ ​org/0000-​ ​0001-6571-​ ​5662 erythematosus. Rev Bras Reumatol Engl Ed 2017;57:583–9. Michelle A Petri http://orcid.​ ​org/0000-​ ​0003-1441-​ ​5373 24 Gomes C, Carvalho JF, Borba EF, et al. Digital vasculitis in systemic lupus erythematosus: a minor manifestation of disease activity? Lupus 2009;18:990–3. 25 Feldman D, Hochberg MC, Zizic TM, et al. Cutaneous vasculitis in REFERENCES adult polymyositis/dermatomyositis. J Rheumatol 1983;10:85–9. 1 Chottawornsak N, Rodsaward P, Suwannachote S, et al. Skin signs 26 Basset-Seguin­ N, Roujeau JC, Gherardi R, et al. Prognostic factors in juvenile- and adult-­onset systemic lupus erythematosus: clues to and predictive signs of malignancy in adult dermatomyositis. A study different systemic involvement. Lupus 2018;27:2069–75. of 32 cases. Arch Dermatol 1990;126:633–7. 2 Drucker AM, Su J, Mussani F, et al. Prognostic implications of active 27 Llamas-­Velasco M, Alegría V, Santos-­Briz Ángel, et al. Occlusive discoid lupus erythematosus and malar rash at the time of diagnosis Nonvasculitic vasculopathy. Am J Dermatopathol 2017;39:637–62. of systemic lupus erythematosus: results from a prospective cohort 28 Carlson JA, Ng BT, Chen K-­R. Cutaneous vasculitis update: study. Lupus 2016;25:376–81. diagnostic criteria, classification, epidemiology, etiology, 3 Santiago-­Casas Y, Vilá LM, McGwin G, et al. Association of discoid pathogenesis, evaluation and prognosis. Am J Dermatopathol lupus erythematosus with clinical manifestations and damage accrual 2005;27:504–28. in a multiethnic lupus cohort. Arthritis Care Res 2012;64:704–12. 29 Alavi A, Hafner J, Dutz JP, et al. Livedoid vasculopathy: an in-depth­ 4 Drenkard C, Villa AR, Reyes E, et al. Vasculitis in systemic lupus analysis using a modified Delphi approach. J Am Acad Dermatol erythematosus. Lupus 1997;6:235–42. 2013;69:1033–42. 5 Ramos-Casals­ M, Nardi N, Lagrutta M, et al. Vasculitis in systemic 30 Bouaziz JD, Barete S, Le Pelletier F, et al. Cutaneous lesions lupus erythematosus: prevalence and clinical characteristics in 670 of the digits in systemic lupus erythematosus: 50 cases. Lupus patients. Medicine 2006;85:95–104. 2007;16:163–7.

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